The goal of this proposal is to study the mechanisms by which insulin-like peptides and the insulin receptor pathway regulate ethanol-induced behaviors in Drosophila and in mice This idea emerged from the convergence of two independent lines of investigation. First, previous genetic screens for Drosophila mutants with altered ethanol sensitivity identified mutations in several components of the insulin receptor signaling pathway. Second, neuroanatomical mapping experiments in Drosophila revealed that a group of insulin producing neurosecretory cells controls normal ethanol sensitivity. We therefore postulate that the insulin pathway, well known for its role in regulating metabolism, growth, and life span, is also involved in the regulation of ethanol-related behaviors. Here we propose to use genetic, and molecular approaches to define how, when, and where insulin functions in ethanol sensitivity in Drosophila and to begin the translation of this information to a mammalian system. First, we will study the role of insulin-producing cells in ethanol-related behaviors. Second, we will use a collection of existing mutants and transgenic fly strains, which are known to inhibit or activate various components of the insulin receptor pathway, to define additional signaling molecules and to establish their functional relationships. Third, we will use inducible gene expression strategies to determine if the insulin pathway functions during development or adulthood to regulate ethanol-induced behaviors. Fourth, we will study the functional relationship between insulin-like peptides and the neuropeptide encoded by the amnesiac gene, which was previously shown to regulate ethanol sensitivity. Finally, we will test if this signaling pathway plays a role ethanol-related behaviors in mice. The role of the insulin pathway in regulating growth, metabolism, and life span has been shown to be conserved from invertebrates to mammals. We predict that this functional conservation will hold for ethanol related phenomena. As drugs that target components of the insulin pathway are already available, information gained from studies in flies and mice could be readily transferred to people with alcohol abuse or alcoholism problems.